1. Field of the Invention
The present invention relates to synthesis of glutamine-containing peptides. More particularly, it relates to a process for the synthesis of glutamine-containing peptides which comprises reacting an N-protected amino acid or peptide with N-hydroxysuccinimide o the like to form an active ester by the use of a condensing agent, such as dicyclohexylcarbodiimide, and subjecting the ester to a reaction with unprotected glutamine in the presence of a weak base, to form a peptide with a C-terminal glutamine, followed by eliminating the N-protective group from the peptide.
2. Description of the Related Art
Glutaimine is an indispensable component of culture media or infusions, but it is very difficult to use glutamine because of its low thermal stability. Glutamine-containing dipeptides exhibit a good thermal stability and can be handled, even at temperature conditions of sterilization.
Glutamine-comtaining dipeptides are highly useful as ingredients for serum-free media. They have also been employed as ingredients for infusions. Their practical importance is thus widespread.
In producing glutamine-containing peptides, it is known that various side reactions are liable to take place due to the instability of the .beta.-amido group of the glutamine residue, thus making their synthesis quite difficult (see, e.g., J. Rudinger, Angew. Chem., 71, 742 (1959)). Other publications concerning the synthesis of glutamine-containing peptides are listed hereinbelow and are incorporated herein by reference.
(1) Y. Shimonishi, S. Sakakibara and S. Akabori, Bull. Chem. Soc. Jap., 35, 1966-1970. PA1 (2) Y. Shimonishi, Bull. Chem. Soc. Jap., 37, 200-203. PA1 (3) S. Akabori, S. Sakakibara and Y. Shimonishi, Bull. Chem. Soc. Jap., 34, 739.
However, the processes described in the above publications involve significant difficulties if they are to be used as commercial processes. In addition, final products obtained by the processes are contaminated with impurities which are difficult to remove. Furthermore, the processes give only poor yields. For example, when applied to the synthesis of alanylglutamine, the process described in (1) above gives a yield of only ca. 5%, and the process described in (3) above provides a yield of at best ca. 28%. The known processes are therefore by no means satisfactory from a commercial point of view.
There remains a need for improved methods of synthesizing glutamine-containing peptides.